The present invention relates to euthanasia compositions which are used for producing humane death in lower mammals. In particular the present invention relates to euthanasia solutions which use the anesthetic gamma-hydroxybutramide (embutramide) as a basis for formulating the composition. (2) Prior Art
Euthanasia compositions for lower mammals are necessary in order to provide humane death. Generally the solutions are injected intravenously or intraperitoneally. Users of such solutions are animal shelters, humane societies, veterinarians, veterinary hospitals, zoos and researchers. The owners of such animals are all concerned with providing a humane death.
Euthanasia compositions containing barbiturates are on the market. These solutions are controlled by the U.S. Drug Enforcement Administration (DEA) because of the barbiturates which are Class II or Class III controlled substances. There is a need for compositions which are not controlled because of the record keeping involved in handling the barbiturate compositions.
The need to formulate a new euthanasia composition was prompted by problems with a euthanasia composition which was marketed under the name "T-61" and is no longer on the market. It is comprised of an anesthetic, gamma-hydroxybutramide; a local anesthetic, tetracaine; a muscle relaxant, mebezonium; and a solvent, dimethylformamide. The composition of this solution contains as solids, 78% gamma-hydroxybutramide; 2% tetracaine; and 20% mebezonium, and as liquids a mixture of 60% dimethylformamide and 40% water. The solution contained 25.5% total solids and the solution has a syrup-like consistency and is injectable with a 22 gauge syringe.
A component of T-61 was causing adverse side effects when the product was rapidly injected intravenously. The physiological and pharmacological effects of each component of the euthanasia solution, T-61 were investigated. The anesthetic, gamma-hydroxybutramide, appeared to be an effective lethal drug at the recommended dose for T-61 (62 mg/kg). Its onset of action occurred within 15 to 25 seconds and has a smooth, calm induction with 47% ethanol used as a vehicle. Mebezonium, the neuromuscular blocking agent included in T-61 was found to be effective at the concentration contained in T-61. The equi-effective dose of mebezonium is about 3 mg/kg and at the volume recommended for euthanasia with T-61, the dose of the muscle relaxant is 15 mg/kg IV. The onset of effect at the equi-effective dose is approximately 75 seconds.
Tetracaine hydrochloride (5 mg/ml; 1.5 mg/kg) appeared to be responsible for bizarre behavioral effects when T-61 was given rapidly. This is a high dosage. This response, e.g., stiffening of the forelimbs, opisthotonos, and an apparent uneasy appearance was reproduced when tetracaine was given alone at the dose contained in T-61. This undesirable effect is most likely due to the direct stimulatory effects of tetracaine on the central nervous system. Tetracaine hydrochloride was recommended to be given slowly. In practice it was given rapidly and produced the undesired behavioral response. The euthanasia solutions approved by the FDA now for marketing do not allow a slow rate of injection since this is unpractical in use.
Dimethylformamide (DMF) is the solvent used in T-61 to keep embutramide in solution. This produces a thick solution. DMF is used at a 60% by volume in water concentration in T-61 and appears to have a local irritating effect at the site of injection. It also appears to have a central stimulating effect which is observed within the first 15 seconds following injection. This is then followed by a period of sedation lasting 15 to 30 minutes in some animals when given alone. It does not appear to alter the onset of anesthesia induced by embutramide nor contribute to the lethal effects of the anesthetic. The 60% concentration of DMF is too high and is most likely responsible for the discomfort induced when T-61 is given rapidly.
An additional problem with the T-61 composition is the appearance of a noticeable heart beat which persists during the euthanasia procedure. Although this activity of the heart is ineffective in perfusing body tissues, it nevertheless is visible in thin chested dogs or small animals and usually persists for many minutes. This is not esthetically pleasing to the owner nor to people performing this task who are not familiar with the time course or lethal effects of hypoxia.
There was thus a need for an improved euthanasia solution. Gamma-hydroxybutramide is not included on the list of drugs controlled by the Federal Drug Enforcement Agency. In addition, it has a rapid onset of action causing almost immediate anesthesia and cessation of breathing. The problem then was to provide an effective formulation which overcomes the problems of the prior art with T-61.
The lethal effects on the heart of chloroquine or quinacrine, which are antimalarial drugs in human beings, have been recognized. So far as is known, there has been no attempt to provide useful euthanasia formulations with these drugs.
In injectable formulations, the effects of potassium on the heart is known (Tona, Lutete, et al., European Journal of Pharmacology 178:293-301 (1990)). This can be seen in Mudge, G. H. Potassium section VII, Water, Salts and Ions. In The Pharm. Basis of Therapeutics, Goodman and and Gilman, Eds., MacMillan Publishing Co., New York, 1985, pp 866-874.